Tetrahydrobiopterin (BH4, sapropterin) controls production of nitric monoxide by the mediation of an endothelial nitric oxide synthase (NOS). Therefore, BH4 is thought to be effective for treating or ameliorating various diseases and pathological conditions in relation to nitric monoxide generated by the mediation of NOS. Such diseases and conditions include, for example, Parkinson's disease, cerebral ischemia, spasm after subarachnoidal hemorrhage, cerebrovascular disorders (e.g., ischemia-reperfusion injury), myocarditis, coronary vasospasm, cardiac hypertrophy, arteriosclerosis, hypertension, thrombosis, infections, endotoxin shock, hepatic cirrhosis, hypertrophic pyloric stenosis, gastric mucosal injury, pulmonary hypertension, renal dysfunction, impotence and hypoglycemia.
Also, BH4 plays an important role in a biosynthesis pathway involving intracerebral neurotransmitters such as serotonin, dopamine, noradrenaline and adrenaline. Previous studies suggest that occurrence of BH4 deficiency in cells causes brain dysfunctions. Such brain dysfunctions include central mental disorders (e.g., phenylketonuria, depression, hyperphagia, autism, attention deficit disorder and cognition disorder) and central movement disorders (e.g., myotonia, stiffness and tremor). However, in the case of peripheral administration, BH4 is blocked by the blood-brain barrier and cannot reach cerebral nervous cells. In this case, the above conditions are not ameliorated.
A recent study has revealed that, as compared with BH4, sepiapterin can more readily pass through the blood-brain barrier to easily enter the tissue. The study has reported that peripherally administered sepiapterin passes through the blood-brain barrier and is converted into BH4 in the brain, whereby elevating the brain BH4 level, and that sepiapterin serves as a useful therapeutic and prophylactic drug for brain dysfunctions (Patent Document 1).
Although BH4 has a wide range of physiological activities, the solubility thereof is considerably high. Thus, a considerable amount of BH4 administered is immediately discharged into urea. Therefore, sepiapterin, which can be readily taken into cells, is thought to have higher bioavailability than BH4. In addition, sepiapterin, which is a naturally occurring product, and its analogues, lactoylpterin and tetrahydrolactoylpterin, have high safety and are envisaged to exhibit various bioactivities.
Sepiapterin is known to be synthesized through a method involving reaction of 7,8-dihydropterin with α-keto-β-hydroxybutyric acid in the presence of zinc chloride (Non-Patent Document 1), and a method involving air-oxidation of BH4 for 6 days (Non-Patent Document 2).
Lactoylpterin is known to be synthesized through oxidation of sepiapterin (Non-Patent Documents 3 and 4).